There are several pathological conditions which involve irregularities in calcium metabolism. Such conditions comprise bone related diseases including Paget's disease and osteoporosis, as well as osteolysis in bone metastases.
Bone metastases present a major problem in many frequently occurring malignancies. Hypercalcemia, resulting from bone resorption, is a common and very important complication of malignancy, causing distressful symptoms, such as severe pain and spontaneous fractures, and may lead to a metabolic coma and death. Moreover, neoplastic cell-induced osteolysis may determine the localization and growth enhancement of the tumor. (G. R. Mundy, Bone, 8, supp. 1, S9-5 16 (1987); Calcium in Biological Systems, R. P. Rubin, G. B. Weiss, and J. W. Putney, Jr. eds. Plenum Press, N.Y. (1985)). Ectopic calcification is a seemingly opposite type of pathological condition, characterized by the deposition of calcium phosphate in a number of clinically important diseases including, for example, atherosclerosis, kidney and renal calculus, arthritis, and bioprosthetic heart valve calcification, and implanted biomaterial calcification such as bioprosthetic and prosthetic heart valves, vascular grafts, LVAD (left ventricular assist devices), contact lenses and entire artificial hearts.
In some common bone disorders, the balance between the process of resorption and formation remains normal, but the rate of bone turnover is much higher. Most cases of primary hyperparathyroidism, Paget's disease and thyroxicosis are in this category. In other common diseases such as osteoporosis, there is an imbalance between resorption and formation. Whether increased resorption or impaired formation predominates, however, the consequence is the same, i.e. diminished total bone mass. This lowering in the bone mass continues until it falls below the critical fracture threshold (B. D. Boyan, "New Therapies for Age-related Bone Disease", Hospital Practice, 26; supp. 1, 1991).
Bisphosphonates are a relatively new class of drugs that have been developed for use in various metabolic diseases of bone, the target being excessive bone resorption and inappropriate calcification and ossification. (M. D. Francis and R. R. Martodam, in "The Role of Phosphonates in Living Systems" R. L. Hilderbrand, ed., CRC Press, Boca Raton, Fla., 1983, pp. 55-96; H. Fleisch, Bone, 1987, 8, Supp. 1, S23-S28). Recently there have been reports of encouraging clinical trials utilizing bisphosphonates to treat osteoporosis and hypercalcemia in patients with breast cancer, myeloma, and bronchial carcinoma related osteolytic metastases, in addition to the established usage of bisphosphonates in Paget's disease and for diagnostic purposes in bone mapping. However, bisphosphonate therapy is frequently accompanied by severe side effects. Bisphosphonates have been also found highly potent both in inhibiting bioprosthetic heart valve calcification, and in experimental arteriosclerosis. However, this was accompanied by severe adverse effects on bone development and overall somatic growth.
Currently used bisphosphonates belong to the geminal type, in which the two phosphoryl groups are bound to the same carbon ("P--C--P"), and therefore may be viewed as pyrophosphate analogs in which the oxygen between the two phosphorus atoms is replaced by a carbon.
In contrast, monophosphonates, vicinal bisphosphonates (P--C--C--P) and compounds in which the distance between the phosphoryl groups is longer (P--(C).sub.n --P, n&gt;2) are reported to be less active or inactive at all.
U.S. Pat. No. 3,012,054 dated Mar. 18, 1960 and M. Kanaan and R. Burgada, Phosphorus and Sulfur, 1988, 37, 217-229, describe the preparation of "tetraalkyl esters of diphosphonates" having the structure: ##STR2## wherein R is an alkyl radical containing 1-4 carbons and n is 2 to 8, inclusive. The cited patent deals only with tetraesters. It is well known that such dialkyl acylphosphonates, as mentioned, exhibit extreme instability toward water, and they hydrolyze to the corresponding carboxylic acids both in acidic and alkaline conditions. Consequently, hydrolysis of the tetraalkyl esters described in the patent and the paper cited above would lead to dicarboxylic acids HOOC--(CH.sub.2).sub.n -- COOH. Therefore, the syntheses of dealkylated derivatives such as represented by the formulas below: ##STR3## require special nonhydrolytic methods, and by no means are the dealkylated compounds obvious derivatives of the tetraesters.
Neither esters nor acids of bisphosphonates in which the two ketophosphonic groups are aromatic rings or the like have been reported.
From the results obtained in various clinical studies using conventional bisphosphonates, it appears that there is a need for compounds which have greater margin between the bone resorption inhibiting effect and that inhibiting mineralization, without an increase in toxicity.